Pulmonary Hypertension
Conditions
Keywords
LVAD
Brief summary
STUDY OBJECTIVES Primary objective To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) as compared to placebo in subjects with pulmonary hypertension (PH) after left ventricular assist device (LVAD) implantation. Secondary objectives To evaluate the effect of macitentan 10 mg as compared to placebo on cardio-pulmonary hemodynamics and disease severity in subjects with PH after LVAD implantation. To evaluate the safety and tolerability of macitentan 10 mg in subjects with PH after LVAD implantation. Exploratory objectives To explore the potential effect of macitentan 10 mg as compared to placebo on right ventricular function in subjects with PH after LVAD implantation. To explore the potential effect of macitentan 10 mg as compared to placebo on selected clinical events in subjects with PH after LVAD implantation. To explore the potential effect of macitentan 10 mg as compared to placebo on renal function as measured by glomerular filtration rate (GFR) in subjects with PH after LVAD implantation.
Interventions
DRUGMacitentan 10mg
2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo
2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written Informed Consent prior to initiation of any study-mandated procedure. 2. Males or females ≥ 18 years of age. 3. Surgical implantation of LVAD within 90 days prior to Randomization. 4. Hemodynamic evidence of PH on Baseline right heart catheterization (RHC) by the thermodilution method. Baseline RHC is defined as the last hemodynamic measurements after LVAD implantation and prior to the first dose of study treatment. PH is defined as: 1. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and 2. Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg and 3. PVR \> 3 Wood units. 5. Stabilization of the patient for 48 h prior to the Baseline RHC, defined as: 1. No LVAD pump speed/flow rate changes and 2. Stable dose of oral diuretics and 3. No intravenous (i.v.) inotropes or vasopressors and 4. Patient able to ambulate. 6. A woman of childbearing potential is eligible only if she has: 1. A negative serum pregnancy test result during the Screening period (Visit 1) and Randomization (Visit 2) and 2. Agreement to undertake monthly serum pregnancy tests during the study and up to 30 days after study treatment discontinuation and 3. Agreement to use one of the methods of contraception / follow the contraception scheme described in Section 4.5 from Screening and up to at least 30 days after study treatment discontinuation. 7. Patient must be randomized within 14 days of Baseline RHC.
Exclusion criteria
1. Documented severe obstructive lung disease defined as: forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC) \< 0.7 associated with FEV1 \< 50% of predicted value after bronchodilator administration. 2. Documented moderate to severe restrictive lung disease defined as: total lung capacity \< 60% of predicted value. 3. Documented pulmonary veno-occlusive disease. 4. Patients undergoing dialysis. 5. Hemoglobin \< 8.5 g/dL at Randomization. 6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 × the upper limit of normal (ULN) at Randomization. 7. Severe hepatic impairment, e.g., Child-Pugh Class C liver disease. 8. Body weight \< 40 kg at Randomization. 9. Doppler mean blood pressure \< 65 mmHg at Randomization. 10. GFR \< 30 mL/min at Randomization. 11. Pregnant, planning to become pregnant during the study period, or breastfeeding. 12. Treatment with endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE5) inhibitors, i.v., subcutaneous (s.c.), or oral prostanoids, or guanylate cyclase stimulators within 7 days prior to Baseline RHC or study treatment initiation. 13. Treatment with inhaled prostanoids (e.g., iloprost, epoprostenol) or nitric oxide within 24 h prior to Baseline RHC or study treatment initiation. 14. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 28 days prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John's Wort). 15. Treatment with strong inhibitors of CYP3A4 within 28 days prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, iopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, and idinavir). 16. Treatment with another investigational drug (planned, or taken) within 28 days prior to study treatment initiation. 17. Known hypersensitivity to ERAs, or to any of the study treatment excipients. 18. Any condition that prevents compliance with the protocol or adherence to therapy. 19. Known concomitant life-threatening disease with a life expectancy \< 12 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline | Baseline to Week 12 | PVR ratio equals to Week 12 PVR / Baseline PVR. PVR represents the resistance against which the right ventricle needs to pump. PVR was calculated using the following formula: mean pulmonary arterial pressure (mPAP) - pulmonary artery wedge pressure (PAWP)/cardiac output (CO); where mPAP and PAWP were measured at end-expiration and CO was measured in triplicate using the thermodilution method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | Baseline to Week 12 | mPAP was collected in the eCRF. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Change from baseline to Week 12 in mPAP was measured at rest and no correction for multiple testing was applied. |
| Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP) | Baseline to Week 12 | PAWP was collected in the eCRF. PAWP is pressure within the pulmonary arterial system when the catheter tip is 'wedged' in the tapering branch of one of the pulmonary arteries. Change from baseline to Week 12 in PAWP was measured at rest and no correction for multiple testing was applied. |
| Change From Baseline to Week 12 in Cardiac Index (CI) | Baseline to Week 12 | CI was calculated as Cardiac Output (CO)/body surface area (BSA), where CO is Thermodilution Cardiac Output (Liters per minute \[L/min\]) and BSA (m\^2) equals to 0.007184\*weight\^0.425 (kilograms)\*height\^0.725 (centimeter). CI was represented in liters per minute per square meter (L/min/m\^2). Change from baseline to Week 12 in CI was measured at rest and no correction for multiple testing was applied. |
| Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | Baseline to Week 12 | mRAP was collected in the eCRF (electronic case record form). Right atrial pressure (RAP) is the blood pressure in the right atrium of the heart. Change from baseline to Week 12 in mRAP was measured at rest and no correction for multiple testing was applied. |
| Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2) | Baseline to Week 12 | Mixed venous oxygen saturation measures the end result of oxygen consumption and delivery. Change from baseline to Week 12 in SvO2 was reported and measured at rest and no correction for multiple testing was applied. |
| Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | Baseline to Week 12 | NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure. |
| Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | Baseline to Week 12 | WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Change from baseline in WHO FC was reported. WHO FC was categorized as worsening (change greater than \[\>\] 0); improvement (change less than \[\<\] 0); or no change (change equals to \[=\] 0). |
| Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | Baseline to Week 12 | TPR was calculated as mPAP/CO where mPAP is mean pulmonary arterial pressure and CO is cardiac output. Change from baseline to Week 12 in TPR was calculated at rest and no correction for multiple testing was applied. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Macitentan 10 Milligrams (mg) Participants (with pulmonary hypertension \[PH\] after a left ventricular assist device \[LVAD\] implantation) received macitentan 10 mg orally once daily up to Week 12. | 28 |
| Placebo Participants (with PH after LVAD implantation) received matching placebo orally once daily up to Week 12. | 29 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Heart Transplant | 1 | 2 |
| Overall Study | Physician Decision | 2 | 2 |
Baseline characteristics
| Characteristic | Macitentan 10 Milligrams (mg) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 8.21 | 58.2 years STANDARD_DEVIATION 6.98 | 57.4 years STANDARD_DEVIATION 7.59 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 11 Participants | 19 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 18 Participants | 34 Participants |
| Region of Enrollment UNITED STATES | 28 Participants | 29 Participants | 57 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 22 Participants | 23 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 28 | 2 / 29 |
| other Total, other adverse events | 24 / 28 | 24 / 29 |
| serious Total, serious adverse events | 16 / 28 | 16 / 29 |
Outcome results
Primary
Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline
PVR ratio equals to Week 12 PVR / Baseline PVR. PVR represents the resistance against which the right ventricle needs to pump. PVR was calculated using the following formula: mean pulmonary arterial pressure (mPAP) - pulmonary artery wedge pressure (PAWP)/cardiac output (CO); where mPAP and PAWP were measured at end-expiration and CO was measured in triplicate using the thermodilution method.
Time frame: Baseline to Week 12
Population: The Full Analysis Set (FAS) included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure. Imputation for missing PAWP value was done using mPAP and CO or with left ventricular end diastolic pressure (LVEDP) values of same visit (if available).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline | 0.585 Ratio | Standard Deviation 0.228 |
| Placebo | Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline | 0.757 Ratio | Standard Deviation 0.2578 |
p-value: 0.015895% CI: [0.5798, 0.9426]ANCOVA
Secondary
Change From Baseline to Week 12 in Cardiac Index (CI)
CI was calculated as Cardiac Output (CO)/body surface area (BSA), where CO is Thermodilution Cardiac Output (Liters per minute \[L/min\]) and BSA (m\^2) equals to 0.007184\*weight\^0.425 (kilograms)\*height\^0.725 (centimeter). CI was represented in liters per minute per square meter (L/min/m\^2). Change from baseline to Week 12 in CI was measured at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Cardiac Index (CI) | 0.093 L/min/m^2 | Standard Deviation 0.468 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index (CI) | 0.041 L/min/m^2 | Standard Deviation 0.4576 |
Secondary
Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
mPAP was collected in the eCRF. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Change from baseline to Week 12 in mPAP was measured at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | -3.84 mmHg | Standard Deviation 8.821 |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | -3.86 mmHg | Standard Deviation 7.982 |
Secondary
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
mRAP was collected in the eCRF (electronic case record form). Right atrial pressure (RAP) is the blood pressure in the right atrium of the heart. Change from baseline to Week 12 in mRAP was measured at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | 0.8 millimeters of mercury (mmHg) | Standard Deviation 5.49 |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | -1.4 millimeters of mercury (mmHg) | Standard Deviation 4.71 |
Secondary
Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2)
Mixed venous oxygen saturation measures the end result of oxygen consumption and delivery. Change from baseline to Week 12 in SvO2 was reported and measured at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2) | 4.260 Percentage of SvO2 | Standard Deviation 17.1523 |
| Placebo | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2) | 4.100 Percentage of SvO2 | Standard Deviation 8.5202 |
Secondary
Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels
NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | 1325.68 nanograms/Liter (ng/L) | Standard Deviation 1214.719 |
| Placebo | Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | 1573.44 nanograms/Liter (ng/L) | Standard Deviation 2327.632 |
Secondary
Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC)
WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Change from baseline in WHO FC was reported. WHO FC was categorized as worsening (change greater than \[\>\] 0); improvement (change less than \[\<\] 0); or no change (change equals to \[=\] 0).
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | Worsening | 2 Participants |
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | No change | 13 Participants |
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | Improvement | 10 Participants |
| Placebo | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | No change | 15 Participants |
| Placebo | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | Worsening | 2 Participants |
| Placebo | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) | Improvement | 8 Participants |
Secondary
Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP)
PAWP was collected in the eCRF. PAWP is pressure within the pulmonary arterial system when the catheter tip is 'wedged' in the tapering branch of one of the pulmonary arteries. Change from baseline to Week 12 in PAWP was measured at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP) | 4.0 mmHg | Standard Deviation 7.86 |
| Placebo | Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP) | 1.0 mmHg | Standard Deviation 4.93 |
Secondary
Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
TPR was calculated as mPAP/CO where mPAP is mean pulmonary arterial pressure and CO is cardiac output. Change from baseline to Week 12 in TPR was calculated at rest and no correction for multiple testing was applied.
Time frame: Baseline to Week 12
Population: The FAS included all participants randomized. Here 'N' (number of participants analyzed) includes all participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 Milligrams (mg) | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | -1.399 Wood Unit | Standard Deviation 2.2515 |
| Placebo | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | -0.993 Wood Unit | Standard Deviation 2.2596 |